1. Field of the Invention
The invention generally relates to cancer treatment, and particularly to the treatment of Hepatocellular carcinoma (HCC) and similar cancers. In particular, the invention provides methods for treating cancers by the inhibition of Late SV-40 Factor (LSF). Inhibition of LSF may be achieved by physical or chemical treatment (e.g., in vivo administration of inhibitors). Experimentation presented herein has shown that LSF is an effective target for cancer therapy.
2. Background of the Invention
Hepatocellular carcinoma (HCC) is one of the five most common cancers worldwide (1). The incidence of HCC is increasing despite a decrease in overall incidence of all cancers (2, 3). In the US, the estimated new cases of HCC for 2008 was 21,370 out of which 18,410 were expected to die (2). The mortality rate of HCC parallels that of incidence since HCC is a tumor with rapid growth and early vascular invasion that is resistant to conventional chemotherapy and no systemic therapy is available for the advanced disease (4). As such, understanding the molecular mechanism of HCC development and progression is imperative to establish novel, effective and targeted therapies for this highly aggressive cancer.
Recent studies have revealed that Astrocyte Elevated Gene-1 (AEG-1) is overexpressed in >90% of human HCC patients, compared to normal liver, and AEG-1 plays a key role in regulating development and progression of HCC (5). The transcription factor Late SV40 Factor (LSF) has been identified as a downstream gene of AEG-1 and it has been demonstrated that LSF mediates, in part, AEG-1-induced resistance to 5-fluorouracil (5-FU) in HCC cells (5, 6). LSF, also known as LBP-1c and TFCP2, regulates diverse cellular and viral promoters (7, 8). A major cellular target of LSF is the thymidylate synthase (TS) gene which encodes the rate limiting enzyme in the production of dTTP, required for DNA synthesis (9). Inhibition of LSF abrogates TS induction and induces apoptosis. Thus LSF plays an important role in DNA synthesis and cell survival. In the liver, LSF is activated by inflammatory cytokines and regulates the expression of acute phase proteins (10, 11). In addition, Inhibition of LSF is known to induce S-phase-dependent apoptosis by downreguating thymidylate synthase expression (15). However, prior to the present disclosure, no studies have linked LSF to cancer or to the process of tumorigenesis. Further, no regulatory elements have previously been described for HCC.